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Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170

https://doi.org/10.1007/s11154-021-09677-7

Mechanisms and management of drug‑induced hyperkalemia

in kidney transplant patients
John G. Rizk1 · Jose G. Lazo Jr.2 · David Quan2 · Steven Gabardi3,4 · Youssef Rizk5 · Elani Streja6 · Csaba P. Kovesdy7 ·
Kamyar Kalantar‑Zadeh6,8

Accepted: 16 July 2021 / Published online: 22 July 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused
by a composite of factors such as medications, delayed graft function, and possibly potassium intake. Managing hyperkalemia
after kidney transplantation is associated with increased morbidity and healthcare costs, and can be a cause of multiple hos-
pital admissions and barriers to patient discharge. Medications used routinely after kidney transplantation are considered the
most frequent culprit for post-transplant hyperkalemia in recipients with a well-functioning graft. These include calcineu-
rin inhibitors (CNIs), pneumocystis pneumonia (PCP) prophylactic agents, and antihypertensives (angiotensin-converting
enzyme inhibitors, angiotensin receptor blockers, beta blockers). CNIs can cause hyperkalemic renal tubular acidosis.
When hyperkalemia develops following transplantation, the potential offending medication may be discontinued, switched
to another agent, or dose-reduced. Belatacept and mTOR inhibitors offer an alternative to calcineurin inhibitors in the event
of hyperkalemia, however should be prescribed in the appropriate patient. While trimethoprim/sulfamethoxazole (TMP/
SMX) remains the gold standard for prevention of PCP, alternative agents (e.g. dapsone, atovaquone) have been studied and
can be recommend in place of TMP/SMX. Antihypertensives that act on the Renin–Angiotensin–Aldosterone System are
generally avoided early after transplant but may be indicated later in the transplant course for patients with comorbidities. In
cases of mild to moderate hyperkalemia, medical management can be used to normalize serum potassium levels and allow
the transplant team additional time to evaluate the function of the graft. In the immediate post-operative setting following
kidney transplantation, a rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Patiromer
and sodium zirconium cyclosilicate (ZS-9) may play an important role in the management of chronic hyperkalemia in kidney
transplant patients, although additional long-term studies are necessary to confirm these effects.

Keywords Hyperkalemia · Potassium · Electrolyte Imbalance · Organ Transplant · Immunosuppression · PCP Prophylaxis ·
Antihypertensives

Abbreviations ECG Electrocardiogram

AP Aerosolized pentamidine GFR Glomerular filtration rate
ACEI Angiotensin-converting enzyme inhibitor PCP Pneumocystis pneumonia
ARB Angiotensin-II receptor blocker RAAS Renin-angiotensin-aldosterone system
CNI Calcineurin inhibitor SPS Sodium polystyrene sulfate
CCB Calcium channel blocker TMP/SMX  Trimethoprim/sulfamethoxazole
CKD Chronic kidney disease ZS-9 Sodium zirconium cyclosilicate

John G. Rizk and Jose G. Lazo Jr. contributed equally to this work.

* John G. Rizk
john.rizk@lau.edu
Extended author information available on the last page of the article

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1158 Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170

1 Introduction
Hyperkalemia, an elevated serum potassium and common
electrolyte abnormality with life-threatening concerns, is
not unique to the kidney transplant recipient, however can
be frequently seen following transplantation [1]. The nor-
mal serum range for serum potassium is 3.5 to 5 mEq/L,
with levels greater than the upper limit of normal defined
as hyperkalemia. The definition and classification of
hyperkalemia varies within the literature, however sever-
ity can be classified by serum potassium levels as mild
(5 to < 6 mEq/L), moderate (6 to 7 mEq/L), and severe
(> 7 mEq/L), and/or with electrocardiogram (ECG) changes
also influencing severity definitions [2, 3]. Besides the pre-
cise potassium level value, acute hyperkalemia is considered
more threatening than chronic stable hyperkalemia. This has
to be taken into consideration when using fixed values for
classification of the severity of hyperkalemia. Of highest
concern is severe hyperkalemia which may manifest with
ECG changes and cardiac arrythmias potentially leading to
death if left untreated. Signs and symptoms of hyperkalemia
are demonstrated in Fig. 1.
Patients with chronic kidney disease (CKD) are at
increased risk for hyperkalemia. A retrospective cohort
study has shown that in a patient with stage 5 CKD, the odds
of hyperkalemia are 11 times more likely than in a patient
with no history of CKD [4]. Prevalent comorbidities such as
diabetes mellitus and hypertension treated with drugs that
affect the renin–angiotensin–aldosterone system (RAAS)
can also place patients at an increased risk for hyperkalemia
[5]. Of note, these two disease states are common comor-
bidities in kidney transplant recipients, with diabetes and
hypertension accounting for the top two etiologies of chronic
kidney disease in adult kidney transplant recipients in 2019
at 33.9% and 22.6%, respectively [6].
Following kidney transplantation, the causes of hyper-
kalemia are multifactorial owing to graft function, excess
potassium intake/repletion, comorbidities, and medica-
tions used in the peri- and post-operative setting [7]. The
acute management of hyperkalemia has been established
for years, however in the setting of nonemergent or chronic
hyperkalemia, innovative therapies have been approved
[8, 9]. In addition, advances in immunosuppression over
the last decade also provide transplant clinicians with
alternatives to lower the risk of hyperkalemia [10]. In this
review, we delve into the etiology and pathophysiology of
hyperkalemia in kidney transplantation and management

Fig. 1  Clinical manifestations

of hyperkalemia. Hyperkalemia
is usually asymptomatic
until cardiac manifestations
develop. These manifesta-
tions usually occur when the
serum potassium concentration
is 6.5—7 mEq/L or possibly at
lower levels with an acute rise
in serum potassium. Although
transplant specific consequences
of hyperkalemia have not yet
been outlined, the most com-
monly affected organs are the
cardiac and skeletal muscles
due to an impairment of neuro-
muscular transmission. Hyper-
kalemia can cause ascending
muscle weakness that begins
with the legs and progresses to
the trunk and arms, and rarely
muscle paralysis, myopathy and
paresthesia

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Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170
strategies for the unique medications used for transplanta-
tion when hyperkalemia occurs.
2 Renal‑mediated mechanisms of potassium
homeostasis
Potassium homeostasis plays a critical role in various
physiologic processes including but not limited to cell
volume regulation, intracellular pH, protein and DNA
synthesis, and maintaining a normal cell membrane
potential. Potassium is predominantly located intracellu-
larly, most commonly within muscles, with only 1 to 2%
present in extracellular fluid [11]. This large intracellular
pool of potassium allows for rapid exchange of extracel-
lular potassium ions to maintain serum potassium within
its normal range.
The renal transport pathways are crucial regulators of
potassium homeostasis. In the proximal tubule, potas-
sium reabsorption is thought to occur primarily via the
paracellular pathway aided by concentration gradient [12].
Moving further along the nephron, the loop of Henle is
responsible for medullary potassium recycling, Potassium
is secreted into the descending thin limbs via passive diffu-
sion from the medullary interstitium which carries a high
potassium concentration [13]. Potassium is then reab-
sorbed along the thick ascending limb via active transport
by apical ­Na+K+2Cl− (NKCC2) and a paracellular path-
way. On the basolateral membrane, potassium crosses into
the interstitium by potassium channels or cotransport with
­Cl− or ­HCO3− [14].
The majority of filtered potassium is reabsorbed within
the proximal tubules and loop of Henle, leaving the distal
nephron with the role of finalizing potassium excretion.
At the distal convoluted tubule, expression of renal outer
medullary K + channels (ROMK) allow for potassium secre-
tion. Within the connecting tubule and the cortical collect-
ing duct, potassium is secreted by a small-conductance
(SK) channel and a large-conductance (BK) channel found
on the apical side [15, 16]. On the basolateral side, the
­Na+-K+-ATPase maintains the resting potential and func-
­ + secretion and N
tions in K ­ a+ absorption at the apical mem-
brane. Within the collecting duct, potassium reabsorption
may occur via apical ­H+/K+-ATPase pumps [17].
The secretion and reabsorption of ­K+ is also affected
by other ions such as ­Na+. Aldosterone is a hormone that
stimulates potassium secretion. Aldosterone increases the
density of apical ­Na+ channels in the connecting tubules
and cortical collecting duct particularly via epithelial
sodium channel (ENaC). The reabsorption of ­Na+ provides
a negative potential difference, which then stimulates ­K+
secretion [18].
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3 Mechanisms of transplant
medication‑induced hyperkalemia
The reported incidence of hyperkalemia is 5–40% among
patients treated with a calcineurin inhibitor (CNI) such as
cyclosporine or tacrolimus [19, 20]. Other immunosup-
pressive agents such as sirolimus, everolimus, mycophe-
nolic acid, azathioprine, belatacept, and prednisone have
not been found to be associated with hyperkalemia [21].
Given that some kidney transplant patients may have a
reduced eGFR, drugs that induce hyperkalemia will mani-
fest more profound effects on potassium levels in these
patients. The exact mechanism in which CNIs induce
hyperkalemia is still unclear, and there are several postu-
lated mechanisms that describe how impaired renal potas-
sium excretion might occur. It is hypothesized that CNIs
activate the sodium-chloride cotransporter in the distal
convoluted tubule through unopposed phosphorylation of
the cotransporter [22]. In addition, CNIs are capable of
inhibiting renal outer medullary K ­ + channels, also known
as ROMK, and Na–K ATPase in the distal tubules. Heer-
ing et al. showed that CNIs induce the down-regulation
of mineralocorticoid receptor expression by inhibiting
mineralocorticoid receptor transcriptional activity (see
Fig. 2) [23]. As a result, these patients develop aldoster-
one resistance that manifests as hyperkalemia and meta-
bolic acidosis, also referred to as Type 4 renal tubular
acidosis [23, 24]. Cyclosporine may also have a second-
ary and additive effect on potassium elevation in patients
concomitantly receiving a beta blocker by a mechanism
that is not understood [25]. Compounding this situation
further is that CNIs are inherently nephrotoxic and have
been increasingly recognized as the main cause of CKD
in transplant patients [26].
The trimethoprim component in trimethoprim/sul-
famethoxazole (TMP/SMX) and pentamidine are struc-
turally similar to amiloride and triamterene [27–29], caus-
ing hyperkalemia by competitively inhibiting the apical
epithelial sodium channels in the distal nephron. Under
normal conditions, it is through these channels that sodium
reabsorption occurs, which then creates an electrical gradi-
ent that favors ­K+ secretion [30]. Inhibition of epithelial
sodium channels reduces the amount of potassium trans-
ported from the cell into the tubular lumen and thus into
the urine. This leads to a decrease in the amount of potas-
sium excreted in the urine and an accumulation of potas-
sium in the serum [27].
Hyperkalemia is a rare side effect of TMP/SMX in
healthy patients, although cases have been reported [31].
The side effect becomes more prominent in patients with
an underlying disorder of potassium metabolism, kidney
insufficiency, or if drugs known to induce hyperkalemia
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1160 Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170

Fig. 2  Schematic overview of

the mechanisms causing hyper-
kalemia in kidney transplant
recipients. Adapted from Rizk
J et al., Curr Opin Nephrol
Hypertens 2021 Jan;30(1):27–
37. Abbreviations: ACEIs,
angiotensin-converting enzyme
inhibitors; ARBs, angiotensin
receptor blockers; ENaC, epi-
thelial sodium channel; ROMK,
renal outer medullary potassium
channel; NCC, sodium chloride
cotransporter; MR, mineralo-
corticoid receptor

are given concomitantly [31]. Kidney transplant patients,
in particular, are considered at high risk for the develop-
ment of hyperkalemia in association with TMP therapy,
and these patients should be monitored closely for the
development of hyperkalemia in part because the major-
ity of kidney transplant patients are on a combination of
TMP/SMX and a CNI [32]. The risk of hyperkalemia is
greater with higher doses of TMP (e.g. treatment doses
of TMP/SMX for pneumocystis pneumonia), although
can also be seen with standard doses. In a case report by
Koc et al., two kidney transplant patients with second-
ary amyloidosis related to familial Mediterranean fever
developed severe hyperkalemia after the administration
of a standard dose of TMP/SMX [32]. Moreover, there is
a major increase in the risk of hyperkalemia when TMP/
SMX is used in combination with angiotensin-converting
enzyme inhibitor (ACEI) or angiotensin-II receptor block-
ers (ARBs), and this adverse event was manifested in a
lung transplant recipient who developed life-threatening
hyperkalemia after treatment with the ACEI enalapril and
TMP/SMX [33]. ACEIs inhibit the conversion of angio-
tensin I to angiotensin II, while ARBs inhibit the action of
angiotensin II produced by all pathways. This results in an
increase in sodium excretion and decrease in kidney loss of
potassium by inhibiting the secretion of aldosterone [32].
There is limited data on the safety and efficacy of aero-
solized pentamidine (AP) in solid organ transplant patients.
Drug-induced hyperkalemia is common in patients receiving
intravenous pentamidine [28, 34, 35]. Macesic et al. pre-
sented the largest retrospective cohort study of 56 kidney
transplant recipients receiving aerosolized pentamidine
[35]. Hyperkalemia was not reported in any of the patients
receiving AP prophylaxis. Similarly, hyperkalemia was not
observed in the retrospective study by Saukkonen et al.
which examined the safety and efficacy of aerosolized pen-
tamidine prophylaxis in 35 adult liver and kidney transplant
recipients [36]. In both of these studies, no patients who
received aerosolized pentamidine developed Pneumocystis
pneumonia (PCP). AP has also been used successfully as
PCP prophylaxis in adults with lung transplants and chil-
dren with liver transplants [37, 38]. In contrast, pentami-
dine is more nephrotoxic in patients with Acquired Immune
Deficiency Syndrome, and hyperkalemia has been reported
in 24% (9/37) of Acquired Immune Deficiency Syndrome
patients receiving a mean pentamidine dose of 255 ± 60 mg/
day, either intravenously or intramuscularly [39]. The sys-
temic absorption of AP is very low [40], about 5%, which
accounts for the higher incidence of hyperkalemia with the
intravenous or intramuscular forms.
4 Managing hyperkalemia by removing
the offending agent
When hyperkalemia develops following transplantation,
the potential offending medication may be discontinued,
switched to another agent, or dose-reduced (Fig. 3). CNIs
are essential to prevent acute rejection and graft loss, and
post-transplant hyperkalemia should be managed despite
keeping patients on these medications. A high tacrolimus

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Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170 1161

Fig. 3  Transplant medication

management strategies for
hyperkalemia. Abbreviations:
angiotensin-converting enzyme
inhibitor (ACEI), angiotensin-
II receptor blocker (ARB),
calcineurin inhibitor (CNI),
calcium channel blocker (CCB),
double strength (ds), single
strength (SS), trimethoprim/sul-
famethoxazole (TMP/SMX)

level (> 20 ng/mL) has been associated with an increased
risk of hyperkalemia [41], thus, routine monitoring of tac-
rolimus trough concentrations is required especially during
first three months after transplant when CNI levels have to
be higher. In addition, foods high in potassium, herbal sup-
plements, potassium-enriched salt substitutes, and drugs that
contain potassium (e.g. penicillin G potassium, phosphorus
replacement products containing potassium, IV solutions
with potassium) should be restricted during the periopera-
tive period, especially in patients at risk [42]. Other drugs
(e.g. heparin [43], succinylcholine [9]) that can cause hyper-
kalemia should also be identified (see Table 1).
4.1 PCP Prophylaxis
The American Society of Transplantation considers TMP/
SMX to be the first-line agent for prevention of PCP and
toxoplasmosis [44]. Additionally, TMP/SMX has the
potential benefit of protecting against other infectious com-
plications in kidney transplant patients [45, 46]. Although
optimal prophylaxis dosing regimens in solid-organ trans-
plant recipients have not been fully defined, the current
recommendation for TMP/SMX use ranges from single
strength (80 mg TMP/400 mg SMX) to double strength
(160 mg TMP/800 mg SMP) orally, either daily or three
times weekly, for at least 6 to 12 months. Adverse effects of
TMP/SMX include hyperkalemia, bone marrow suppression,
elevated serum level of creatinine, and rash [44].
TMP-induced hyperkalemia is dose dependent [30], and
these effects become more prominent when a daily double-
strength regimen is used. Other prophylaxis antimicrobial
agents such as atovaquone, dapsone, and inhaled pentami-
dine are not considered first-line agents by the American
Society of Transplantation because of their narrower spec-
trum of activity, tolerability, cost, and efficacy [44].
Among medications used for the prevention of PCP,
TMP/SMX and pentamidine are the most commonly associ-
ated with hyperkalemia [27, 28, 30, 47–49]. A single-center,
retrospective cohort study examining the tolerability of
TMP/SMX within the first year of kidney transplant showed
that a TMP/SMX regimen of 1 single-strength tablet 3 times
weekly is better tolerated in terms of adverse events than
the double-strength and single-strength daily regimen [50].
Thus, a reasonable practice that can help in reducing the

Table 1  Medications associated Medications Utility in kidney transplantation

with hyperkalemia in kidney
transplantation ACEI and ARB Hypertension
Beta-blockers (non-selective and beta 2-selective) Hypertension
Potassium-sparing diuretics (amiloride, triamterene, Hypertension
spironolactone)
Trimethoprim, pentamidine PCP prophylaxis
Heparin Prevent clot formation during transplant procedure
Succinylcholine Used in transplant recipients in need for rapid
sequence intubation and rapid airway control
Calcineurin inhibitors (cyclosporine, tacrolimus) Immunosuppressive agents
NSAIDs Headache or pain

ACEI angiotensin-converting-enzyme inhibitors, ARB angiotensin II receptor blockers, NSAIDs nonsteroi-

dal anti-inflammatory drugs, PCP Pneumocystis pneumonia

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1162
incidence of hyperkalemia is to decrease the dose of TMP/
SMX from a double-strength to a single-strength tablet three
times weekly when used as prophylaxis for PCP and urinary
tract infections. A different retrospective single-center study
showed that single-strength TMP/SMX thrice weekly is at
least as effective as daily TMP/SMX for PCP prophylaxis in
kidney transplant recipients, and that PCP did not occur after
dose reduction at least during the rest of the first post-kidney
transplant year [51]. To confirm these results, a clinical trial
on transplant recipients comparing daily single strength to
thrice weekly single strength TMP/SMX is needed.
Another strategy is to use dapsone or atovaquone as
alternatives for PCP prophylaxis. Both of these agents are
less likely to cause hyperkalemia and are potential alternate
agents in patients with documented hyperkalemia second-
ary to TMP/SMX [52–55]. Atovaquone dosage should be
1500 mg by mouth once daily given with food, whereas dap-
sone is given at a dose of 50 mg twice daily or 100 mg once
daily [56, 57]. Although patients who receive atovaquone
instead of TMP/SMX for PCP prophylaxis have lower rates of
hyperkalemia, they experience higher rates of recurrent uri-
nary tract infections (UTIs) (33% vs 7%, p = 0.02) [50]. Thus,
routine addition of a UTI prophylactic agent for patients una-
ble to get TMP/SMX and removal of ureteral stents within
the first 30 days after transplantation is essential, particularly
in kidney recipients [50, 58]. McLaughlin et al. showed that
a re-challenge with TMP/SMX after switching to atovaquone
was successful in a patient who previously developed TMP/
SMX-induced hyperkalemia (­ K+ = 6.4 mmol/L) [54]. Fur-
thermore, the routine use of dapsone is not recommended
given the potential for adverse hematologic events such as
hemolytic anemia and methemoglobinemia [52, 59, 60].
TMP/SMX has the concurrent effect of preventing toxo-
plasmosis and some Gram-negative infections [61]. One
double-strength TMP/SMX tablet daily confers protection
against toxoplasmosis [50]. Lower doses of TMP/SMX
may also provide protection against toxoplasmosis, but ran-
domized controlled trials evaluating this option are lacking
[62]. Interestingly, two single-center, retrospective cohort
studies in which kidney transplant patients received single-
strength TMP/SMX thrice weekly did not document any
episodes of Toxoplasma gondii during a 1-year follow-up
[50, 51].
In patients without hyperkalemia, AP is frequently
used as a second-line agent for PCP prophylaxis at a dose
of 300 mg/month preceded by inhaled albuterol, 180 mcg
[35, 36]. It is a useful alternative for PCP prophylaxis in
organ recipients given that it is administered monthly and
has fewer adverse effects than other therapies [36, 37]. The
most common reasons for using AP instead of TMP/SMX
for PCP prophylaxis include prior sensitivity to TMP/SMX
(i.e. rash, anaphylaxis, angioedema), kidney impairment,
and leukopenia [35]. Macesic et al. showed that adverse
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reactions related to the use of AP required hospitalization
and discontinuation of the drug in 5 of 56 (9%) patients;
4 patients had bronchospasm, 1 patient required intensive
care admission for epinephrine infusion, but none developed
hyperkalemia [35]. Thus, TMP/SMX remains the primary
recommended treatment and prophylaxis regimen for PCP
[63], as no patients receiving TMP/SMX required hospitali-
zation [35]. A re-challenge with TMP/SMX was done and
successful in 17 of 22 patients (77%); 3/22 (14%) and 2/22
(9%) failed the re-challenge due to leukopenia and kidney
impairment, respectively.
4.2 Immunosuppressive drugs
U.S. randomized trials showed that 45% of liver transplants
treated with tacrolimus develop hyperkalemia, while 31% of
kidney transplant recipients receiving tacrolimus develop mild
to severe hyperkalemia [64, 65]. Similarly, 26% and 32% of
liver transplant and kidney transplant patients, respectively,
on a cyclosporine-based immunosuppressive regimen devel-
oped hyperkalemia [64, 65]. Conversion from a CNI to other
agents such as an mTOR inhibitor or belatacept can decrease
the incidence of hyperkalemia, but require increased immune
monitoring and may not be appropriate for all patients.
Sirolimus is a potent immunosuppressive agent approved
by the FDA for kidney transplantation in 1999 [66]. Two
randomized, double-blind, placebo-controlled, phase III tri-
als assessing the safety and efficacy of sirolimus reported a
low incidence of hyperkalemia in kidney transplant patients
receiving sirolimus that is not dependent on the dose of the
drug [67, 68]. The incidence of hyperkalemia in patients
receiving sirolimus 2 mg/day was 13% in both trials, and
10–11% in patient groups receiving sirolimus 5 mg/day
[67, 68]. In addition, Johnson et al. have showed previously
that patients on a sirolimus-cyclosporine-steroid regimen
had higher incidence of hyperkalemia than those who had
cyclosporine eliminated from their regimen (2.8% vs 0%,
p = 0.030) [69]. This suggests that the early elimination of
cyclosporine from a sirolimus-cyclosporine-steroid regi-
men can reduce the incidence of hyperkalemia. Conversion
from a CNI-based immunosuppression to an everolimus-
based immunosuppression may also lower the incidence
of hyperkalemia. A prospective, randomized, multicenter
trial revealed that only 8.3% of liver allograft recipient who
started everolimus therapy with CNI reduction or discon-
tinuation developed hyperkalemia [70]. Additionally, a post
hoc analysis by Chapman et al. showed that early everoli-
mus plus reduced-dose tacrolimus had a lower incidence of
hyperkalemia than a standard tacrolimus regimen (7.7% vs
20.5%) at 12-month and 24-month follow-up [71].
Belatacept is a selective T-cell co-stimulation blocker
that is frequently used as a component of a CNI-free triple
drug regimen, often used in conjunction with prednisone and
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mycophenolic acid. Results from BENEFIT and BENEFIT-
EXT (Belatacept Evaluation of Nephroprotection and Effi-
cacy as First‐line Immunosuppression Trial from living
donor or standard criteria deceased donors, and extended
criteria donors, respectively) found that the incidence of
hyperkalemia was similar to cyclosporine [72, 73]. How-
ever, these studies did not specifically look at potassium lev-
els. Belatacept may be associated with less hyperkalemia as
there are no known mechanisms for this drug to induce high
potassium levels, above and beyond improvements in renal
function reported after conversion from CNI to belatacept
that can make hyperkalemia less likely [74, 75].
4.3 Antihypertensive agents
Hypertension is the most common clinical problem among
transplant patients, affecting at least 90% of this popula-
tion [76]. Post-transplant hypertension occurs as a result of
volume overload, CNIs, and vasoconstriction, with vasocon-
striction occurring due to an increase of renin-angiotensin
system, up-regulation of endothelin-1 and reduction of the
bioavailability of nitric oxide [77, 78]. The use of antihyper-
tensive agents in transplant recipients is necessary because
inadequate control of post-transplant hypertension is asso-
ciated with an increased risk of cardiovascular morbidity
and mortality, and graft loss [79]. KDIGO guidelines rec-
ommend that blood pressure in chronic kidney disease and
transplant patients should be kept below or equal of 130/85
and 125/75 in patients with proteinuria [80, 81]. There is
no ideal single agent for the management of post-transplant
hypertension, as there are no randomized controlled trials to
support the use of one agent over another [82].
RAAS blockers may improve arterial hypertension, pro-
teinuria, and erythrocytosis [83, 84]. There remains much
debate regarding the use of these agents in kidney transplan-
tation [83]. Two meta-analyses studies demonstrated that
RAAS blockers are associated with better patient and graft
survival in kidney transplant recipients, but the risk of life-
threatening hyperkalemia is at least three-fold higher when
compared to recipients not receiving these medications [85,
86]. Findings from a meta-analysis by Pisano et al. showed
that ACEIs reduced the risk for graft loss but decreased
kidney function [85]. In addition, ACEIs increased serum
potassium [134 patients; mean difference (MD) 0.33 mEq/L
(95% CI 0.10–0.55) as well as hyperkalemia episodes [418
patients; relative risk (RR) 3.66 (95% CI 1.13–11.80). In
ARB versus placebo/routine treatment, no differences in
graft loss was documented. The effect of ARBs on glo-
merular filtration rate (GFR) was inconclusive. Expectedly,
ARBs increased the risk for hyperkalemia episodes [281
patients; RR 4.10 (95% CI 1.05–15.95)]. Pooled data drawn
from ACEIs and ARBs show that the risk for graft failure
was significantly reduced with respect to placebo/routine
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treatment, but the risk of hyperkalemia was maintained
[681 patients; RR 3.42 (95% CI 1.41–8.29)] [85]. Due to
the scarcity of data, the decision to use or avoid a RAAS
blocker is based on clinical practice rather than scientific
evidence. Patient awareness of hyperkalemia risk associated
with RAAS blockers should be improved, with emphasis on
pre-emptive discontinuation when an acute illness or volume
depletion occurs. Beta-blockers have a demonstrated efficacy
in controlling blood pressure in transplant patients [86].
Beta-blockers can increase plasma potassium levels, a
cause of hyperkalemia often ignored in clinical practice. The
reported incidence of beta-blocker–induced hyperkalemia
is less than 5% [87], although there is little evidence that
they consistently increase potassium levels. The use of non-
selective beta-blockers (e.g. propranolol, nadolol, sotalol) is
associated with metabolic issues, such as hyperkalemia [88].
In contrast, vasodilating beta-blockers with alpha-1 blocking
properties (e.g. carvedilol, labetalol, bucindolol) may be bet-
ter tolerated and may have fewer associated metabolic con-
sequences compared with non-selective beta-blockers [88],
although cases of severe hyperkalemia in kidney transplant
patients taking labetalol have been reported [89, 90]. Moreo-
ver, hyperkalemia is more likely to occur in nonselective
beta-blockers than cardio-selective beta-blockers (e.g. ateno-
lol, metoprolol, bisoprolol) [91].
Calcium channel blockers (CCBs) could be the pre-
ferred first-step antihypertensive agents in kidney trans-
plant patients, as they are associated with a lower incidence
of hyperkalemia and serum potassium levels compared to
RAAS blockers [274 patients; MD -0.24 mEq/L (95% CI
-0.38 to -0.10)], improved graft function, and reduced graft
loss, above and beyond their effect on reducing blood pres-
sure [85]. Head to-head trials displayed that subjects rand-
omized to CCB had improved kidney function, showing a
higher GFR (+ 11 mL/min), and lower serum creatinine lev-
els (-0.12 mg/dL) as compared with the ACEI group. Often,
controlling post-kidney transplant hypertension is challeng-
ing and the majority of patients remain uncontrolled despite
pharmacological management, necessitating the combina-
tion of a CCB with a RAAS blocker or diuretic/thiazide.
Thus, there is an ongoing controversy regarding the routine
use of RAAS blockers in the immediate post-transplant set-
ting due to increases in serum creatinine and the risk of
adverse events.
Diuretics are not routinely used as first line therapy in kid-
ney transplant recipients, as they may cause volume deple-
tion, electrolyte disturbances, and may worsen renal allograft
function [92]. However, their use is important particularly
in the peri-transplant setting. In patients with a good urinary
output, loop diuretics and thiazide diuretics can be adminis-
tered to increase urinary potassium elimination. The diuretic
effects of thiazides were historically considered relatively
weak and not comparable to the more potent actions of loop
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1164
diuretics. Because transplant patients on a CNI commonly
have hyperkalemia, thiazides may increase serum magne-
sium when used with a CNI [92]. A longitudinal retrospec-
tive cohort study conducted in adult kidney transplant recipi-
ents showed that thiazides appear to be safe and effective in
managing hypertension following transplantation, but the
risk of hyperkalemia was higher in the thiazide group than
the unexposed group (56% vs. 38%, p < 0.001) [93]. The
rates of severe hyperkalemia were similar in both groups. In
contrast, a more recent randomized non-inferiority crossover
trial did not report a higher incidence of hyperkalemia in
kidney transplant patients on thiazides compared to those on
a CCB [94]. Perioperative hyperkalemia might be followed
by hypokalemia due to the use of diuretics and fluid resusci-
tation, thus caution is warranted [95]. The use of potassium-
sparing agents (e.g. amiloride, triamterene, spironolactone)
should be avoided in transplant patients at risk of hyper-
kalemia. More RCTs are required to define the efficacy and
safety of loop diuretics in kidney transplant recipients.
5 Treatment of hyperkalemia
In the immediate post-operative setting following kidney
transplantation, a rapidly rising potassium refractory to
medical therapy can be an indication for dialysis. In cases of
mild to moderate hyperkalemia, medical management can be
considered to normalize serum potassium levels and allow
the transplant team additional time to evaluate the function
of the graft [96]. An in-depth review on the management of
acute hyperkalemia is beyond the scope of this review arti-
cle however a brief overview will be provided here; readers
are referred to previously published reviews for a complete
review [2, 9]. Treatment for hyperkalemia can be classified
into three categories: (1) antagonism of the cardiac effects
of hyperkalemia; (2) redistribution of potassium into cells;
and (3) removal of potassium from the body.
Administration of calcium either as calcium chloride or
calcium gluconate should be used in the emergency manage-
ment of hyperkalemia to stabilize the myocardial membrane
from undesirable depolarization [97–99]. The administration
of calcium minimally lowers serum potassium levels, if at
all [7]. Following stabilization of the membrane potential,
the focus shifts towards lowering serum potassium. Insulin
shifts potassium intracellularly within skeletal myocytes and
hepatocytes [100]. A dose of 10 units of regular insulin can be
administered with a bolus or infusion of dextrose to prevent
hypoglycemia. Beta2-adrenergic agonists, such as inhaled
albuterol will exert its effect via Na–K ATPase to decrease
serum potassium [98]. Sodium bicarbonate mediates its effect
on potassium by an increase in serum pH, causing an intracel-
lular shift of potassium via ­H+/K+ exchange [101]. Over the
years, the efficacy of sodium bicarbonate for hyperkalemia
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Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170
has been called into question and should be avoided as mono-
therapy for the treatment of hyperkalemia [102].
Removal of potassium from the body can take place in
the kidneys and the gastrointestinal tract. Loop diuretics are
commonly used in patients’ who have sufficient residual kid-
ney function to allow for an increase in urine output [103,
104]. Loop diuretics are effective for the acute management
of hyperkalemia but may be less preferred for chronic man-
agement. Mineralocorticoids have been used to treat chronic
hyperkalemia in kidney transplant patients treated with cal-
cineurin inhibitors [105, 106]. Fludrocortisone, a synthetic
glucocorticoid with potent mineralocorticoid activity should
be used cautiously as it may elevate blood pressure [107].
Intestinal potassium binders work through cation exchange
using nonabsorbable resins. The classic agent in this class is
sodium polystyrene sulfate (SPS) which exchanges ­Na+ for ­K+
within the colon [108]. SPS is not selective for potassium and
as a result magnesium and calcium may also be eliminated
potentially causing hypocalcemia or hypomagnesemia [7]. Of
note, SPS carriers a risk of intestinal necrosis, particularly
when used in conjunction with sorbitol and may be avoided by
certain clinicians in the early post-op period, particularly now
with novel agents made readily available [109, 110].
Patiromer and sodium zirconium cyclosilicate (ZS-
9) are two novel potassium binders which have recently
become available for the management of hyperkalemia
[111, 112]. Patiromer works as a non-absorbable resin
which exchanges calcium for potassium in the gastro-
intestinal tract [111]. Patiromer has also been shown to
bind to magnesium causing hypomagnesemia in patients
receiving therapy. The recommended dose is 8.4 g once
daily, increasing by 8.4 g weekly up to a maximum of
25.2 g daily, titrating to the desired K ­ + level. The largest
study of patiromer in the solid organ transplant popula-
tion was a retrospective cohort of 37 patients, 26 of which
were kidney transplants, which demonstrated a statisti-
cally significant decrease in K ­ + levels from 5.4 mEq/L at
baseline to 4.99 mEq/L at week 4 and 5 mEq/L at week 12
[113]. ZS-9 works by exchange of hydrogen and sodium
ions for potassium [112]. The recommended dose is 10 g
three times daily for up to 48 h followed by a maintenance
dose of 10 g daily for continued treatment. Dosing may be
increased by 5 g up to 15 g once daily. Of note, every 5 g
of ZS-9 contains 400 mg of sodium which places patients
at risk for developing edema. ZS-9 use in the transplant
population was reviewed in a retrospective cohort of 35
patients, 16 with kidney transplants, and demonstrated a
mean decrease in ­K+ of 1.3 mEq/L from day 0 to day 7
[114]. It is important to recognize that all of these gas-
trointestinal exchange agents have the potential to impact
absorption and should be separated from other medications
according to their respective package insert labeling, SPS
and patiromer, 3 h before and after other oral medications
 Table 2  Clinical studies of patiromer and ZS-9 in transplant patients with hyperkalemia
Drug Investigators Design Transplant population Endpoints Results

Patiromer Singh et al Retrospective, single-center study 37 SOT patients: kidney (73%), liver Primary: Change in ­K+ levels from Statistically significant improvement in
(21%), kidney-pancreas (3%), lung baseline to 4, and 12 weeks; difference ­K+ levels (baseline ­K+ = 5.44) at week
(3%) in tacrolimus levels at baseline, 4, and 4 ­(K+ = 4.99) and week 12 (­ K+ = 5).
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12 weeks Statistically significant increase in

Patiromer Lim et al
Retrospective, single-center study 19 kidney transplant recipients
Secondary: GI side effects, electrolyte
abnormalities, insurance coverage of
patiromer
Safety, effectiveness, and tolerability of All adherent patients had ­K+ lev-
patiromer
tacrolimus levels (7.19 to 9.22 ng/mL)
at week 4. No reported GI side effects,
constipation in 8%. 81% obtained insur-
ance coverage
els < 5.2 mmol/L at last follow-up. 7
patients required tacrolimus dose reduc-
tion within 1–4 weeks of patiromer
initiation; 6 were previously on SPS and
Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170

1 with prior supratherapeutic levels. No

Patiromer Rattanavich et al Not described 2 kidney transplant recipients Effect of patiromer on treating hyper-
kalemia and on tacrolimus trough
levels
ZS-9 Winstead et al Retrospective, single-center study 35 SOT patients: 16 kidney (45.7%), 14 Primary: Change in K ­ + from day 0 to
liver (40%), 2 heart (5.7%), 2 kidney- day 7
liver (5.7%), 1 kidney-heart (2.9%) Secondary: Change in tacrolimus, ­Na+,
and bicarbonate levels from day 0 to
day 7 and any reported adverse events
intolerable side effects; 2 had consti-
pation, 1 had diarrhea, 1 required an
emergency room visit for hyperkalemia
during patiromer dose adjustment
Patiromer use is effective in treating
hyperkalemia and does not affect tac-
rolimus tough levels. Patient 1: hyper-
kalemia resolved within days with ­K+
levels between 4.0–5.5 mEq/L. Patient
2: hyperkalemia resolved but returned
upon patiromer discontinuation with K ­ +
levels between 5.5–6.5 mEq/L. No need
for tacrolimus dose adjustment
K+ levels decreased by -1.3 mEq/L
from day 0 to day 7. Mean change
in concentrations from days 0
to 7: tacrolimus = -0.54 ng/mL,
­Na+ =  + 1.7 mEq/L, bicarbo-
nate =  + 1.6 mEq/L. Two reports of
mild edema
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K + potassium, Na + sodium, SOT solid organ transplant, SPS sodium polystyrene sulfonate, ZS-9 sodium zirconium cyclosilicate

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1166
and ZS-9 separated 2 h before and after oral medications
with clinically meaningful gastric pH-dependent bio-
availability [7]. The current data on the use of these two
potassium binders in the kidney transplant population is
sparing and further high-quality research needs to be con-
ducted to further characterize their effect on immunosup-
pressive medications. At this time, selection between the
two agents should be based on safety profile or formulary
restrictions within individual institutions. Table 2 provides
a summary of studies that investigated the use of these two
potassium binders in the transplant population.
6 Conclusion
The etiology of hyperkalemia in the kidney transplant recipi-
ents can be caused by a composite of factors [7]. CNIs, PCP
prophylactic agents, and antihypertensives are prescribed
almost universally in the transplant recipient [6, 82, 115].
Belatacept offers an alternative to calcineurin inhibitors
however should be prescribed in the appropriate patient [10].
TMP/SMX remains the gold standard for prevention of PCP
however alternative agents have been extensively studied
and can be recommend in place of TMP/SMX [115]. Anti-
hypertensives that act on the RAAS are generally avoided
early after transplant however may be indicated later in the
transplant course for patients with comorbidities.
Monitoring of potassium post transplantation is essential,
while hyperkalemia early after transplant should be treated
urgently as to prevent the need for dialysis. The agents used
for treatment in the acute setting have been established, how-
ever hyperkalemia occurring in the chronic or outpatient set-
ting can now be managed with novel intestinal potassium
binders. Patiromer and ZS-9 will play a significant role in
the management of chronic hyperkalemia and their use will
become widespread upon addition to insurance and institu-
tional formularies. An understanding of kidney transplanta-
tion, the elapsed time from surgery, from hour to weeks to
months, and the mechanisms for medication induced hyper-
kalemia are all necessary to effectively manage this common
electrolyte abnormality.
Declarations
Conflict of Interests JGR, JGL, DQ, SG, YR, ES report they have no
conflicts of interest to disclose relative to this research. CPK is a con-
sultant for Akebia, Ardelyx, Astra-Zeneca, Bayer, Cara Therapeutics,
Reata, Tricida. KKZ has received honoraria and/or support from Abbott,
Abbvie, ACI Clinical (Cara Therapeutics), Akebia, Alexion, Amgen,
Ardelyx, American Society of Nephrology (ASN), Astra-Zeneca, Aveo,
BBraun, Chugai, Cytokinetics, Daiichi, DaVita, Fresenius, Genentech,
Haymarket Media, Hofstra Medical School, International Federation
of Kidney Foundations (IFKF), International Society of Hemodialysis
(ISH), International Society of Renal Nutrition and Metabolism (IS-
13
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Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170
RNM), Japanese Society of Dialysis Therapy (JSDT), Hospira, Kabi,
Keryx, Kissei, Novartis, OPKO, National Institutes of Health (NIH),
National Kidney Foundation (NKF), Pfizer, Regulus, Relypsa, Resver-
logix, Dr Schaer, Sandoz, Sanofi, Shire, Veterans’ Affairs (VA), Vifor,
UpToDate, and ZS-Pharma.
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1170 Reviews in Endocrine and Metabolic Disorders (2021) 22:1157–1170

Authors and Affiliations

John G. Rizk1 · Jose G. Lazo Jr.2 · David Quan2 · Steven Gabardi3,4 · Youssef Rizk5 · Elani Streja6 · Csaba P. Kovesdy7 ·
Kamyar Kalantar‑Zadeh6,8

1 6
Arizona State University, Edson College, Phoenix, AZ, USA Department of Medicine, Division of Nephrology,
2 Hypertension and Kidney Transplantation, School
UCSF Medical Center, University of California San
of Medicine, University of California, CA, Irvine, Orange,
Francisco, San Francisco, CA, USA
USA
3
Department of Transplant Surgery, Brigham and Women’s 7
Division of Nephrology, University of Tennessee Health
Hospital, Boston, MA, USA
Science Center, Memphis, TN, USA
4
Department of Medicine, Harvard Medical School, Boston, 8
Department of Epidemiology, University of California,
MA, USA
UCLA Fielding School of Public Health, Los Angeles, CA,
5
Department of Internal Medicine, Division of Family USA
Medicine, Lebanese American University Medical Center –
St. John’s Hospital, Beirut, Lebanon

13